The present invention relates to a composition and method for regulation of body weight and conditions related thereto, and particularly, to uses of proopiomelanocortin (POMC) peptides and analogs thereof to control body weight and conditions related thereto.
The regulation of body weight, and particularly, obesity and conditions related thereto, is a major health concern throughout the world, and particularly in the United States, contributing to morbidity and mortality. Obesity is a metabolic disorder characterized by excessive accumulation of fat stores in adipose tissue. In humans, its causes are a complex interplay of genetics, environment and culture. It is well known that a regimen of diet and exercise leading to weight loss is the best approach for treating obesity, but unfortunately, such regimens are frequently unsuccessful. Oftentimes, an individual""s inability to lose weight may be due to genetically inherited factors that contribute to increased appetite, a preference for high calorie foods, reduced physical activity and an abnormal metabolism. People inheriting or acquiring such predispositions are prone to obesity regardless of their efforts to combat the condition.
On the other side of the spectrum of body weight problems, other individuals suffer from one or:more xe2x80x9cwastingxe2x80x9d disorders (e.g., wasting syndrome, cachexia, sarcopenia) which cause undesirable and/or unhealthy loss of weight or loss of body cell mass. In the elderly as well as in AIDS and cancer patients, wasting disease can result in undesired loss of body weight, including both the fat and the fat-free compartments. Wasting diseases can be the result of inadequate intake of food and/or metabolic changes related to illness and/or the aging process. Cancer patients and AIDS patients, as well as patients following extensive surgery or having chronic infections, immunologic diseases, hyperthyroidism, extraintestinal Crohn""s disease, psychogenic disease, chronic heart failure or other severe trauma, frequently suffer from wasting disease which is sometimes also referred to as cachexia, a metabolic and, sometimes, an eating disorder. Cachexia is additionally characterized by hypermetabolism and hypercatabolism. Although cachexia and wasting disease are frequently used interchangeably to refer to wasting conditions, there is at least one body of research which differentiates cachexia from wasting syndrome as a loss of fat-free mass, and particularly, body cell mass (Mayer, 1999, J. Nutr. 129(1S Suppl.): 256S-259S). Sarcopenia, yet another such disorder which can affect the aging individual, is typically characterized by loss of muscle mass. End stage wasting disease as described above can develop in individuals suffering from either cachexia or sarcopenia.
In addition to the obvious health risks associated with being overweight or underweight, the tangential detrimental effects of such conditions are equally troublesome. For the obese individual, health effects can include a myriad of physical conditions related to, or affected by, excess body weight (e.g., cardiovascular disease, diabetes, cancer, hypertension, etc.) as well as physiological damage due to an overweight person""s loss of self-esteem, depression, etc. For example, obesity, and particularly upper body obesity, is frequently associated with NIDDM. Non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes) is a metabolic disorder that is characterized by the failure of body tissues to store carbohydrates at a normal rate. Resistance to the action of insulin is the most common characteristic of a Type II diabetic. When this resistance exceeds the capacity of the insulin-producing beta cells of the Islets of Langerhans to produce insulin, clinical diabetes results. In addition to NIDDM, being overweight, even in the absence of clinical obesity, can significantly increase the risk of developing certain other conditions, and/or of exacerbating the symptoms associated with the condition once developed. For example, the risk of inquiring several forms of cancer is increased in obese patients. Such cancers include breast cancer and colon cancer. Moreover, it has been known for years that excess body weight can be a risk factor for cardiovascular disease, hypertension, stroke and gall bladder disease. Obesity can also contribute to the risk of acquiring, or exacerbating, respiratory problems and osteoarthritis.
Other conditions that are frequently associated with excess gain of body weight are affective and mood disorders, including atypical depression or dysthymia. Some patients may alternatively experience undesired loss of body weight. It has previously been shown that in patients with an affective disorder characterized by higher than normal levels of HPA axis activity, leptin levels are also increased from normal levels in the blood of such patients (U.S. Pat. No. 5,866,547 to Flier et al., incorporated herein by reference in its entirety). High cerebrospinal fluid (brain) leptin levels are needed to suppress the increased activity of the HPA axis in these patients.
Another factor which can significantly contribute to an individual""s propensity to gain weight and/or an inability to lose weight may be a side effect associated with one or more pharmaceutical compounds that the individual is taking to treat another condition. For example, epilepsy, attention deficit hyperactivity disorder (ADHD), and recently, migraine, are often treated with the drug, valproic acid, also known commercially as Depakote, which has the well known and undesirable side affect of increasing body weight. Other drugs having a similar side effect include lithium, commonly used for bipolar disorder (manic depression) and a several other antidepressants, including tricyclic antidepressants and several selective serotonin reuptake inhibitors (SSRIs) including fluoxetine, also known commercially as Prozac. There are a number of other drugs which have similar side effects, or the opposite side effect (i.e., undesired loss of body weight), including many drugs used for chemotherapy. Indeed, Such side effects can have serious implications for the patient""s compliance with the drug therapy, as well as the patient""s general well being and health. Indeed, many patients are likely to choose a lower body weight and greater self esteem over the treatment of what can be a disabling and destructive disorder, which reduces the ability of both patient and physician to maintain control over the disorder. When the disorder is a bipolar disorder, for example, non-compliance can be life-threatening.
For the underweight individual, conditions related to or affected by low body weight can include heart failure, susceptibility to infectious disease as a result of immune system weakness, and depression. Moreover, the rise in bulemia and anorexia in the past few decades is alarming, and illustrates the disturbing emphasis on ideal body size and shape regardless of the severe health consequences.
In 1963, Kennedy and Mitra proposed that puberty is linked to body weight and more specifically, to fat storage which is concluded to be one of the signals responsible for the initiation of hypothalamic control of ovarian function (J. Physiol. 166:408). Other researchers have proposed that the loss or restoration of menstrual cycles in young girls is related to a minimum weight for height (Frisch and McArthur, 1974, Science 185:949). Frisch and McArthur proposed that normal girls become relatively fatter from menarche to reproductive maturity. Taken together, these studies indicate that there is a relationship between the initiation of reproduction and adiposity. In support of this relationship were the observations that very lean young female ballet dancers and college rowers have a delayed puberty (Frisch et al., 1980, NEJM 303:17 and Frisch et al., 1981 ,JAMA 246:1559), whereas obese girls have an acceleration of puberty (Zacharias et al., 1970, Am. J. Obs. Gyn. 108:833). The amenorrhea of extremely lean women was attributed to loss of fat and hypothalamic dysfunction (Vigersky et al., 1977, NEJM 297:1141). Based on such studies, Frisch et al. formed a hypothesis that a metabolic signal may be responsible for the initiation of reproduction, or the xe2x80x9ccritical weightxe2x80x9d hypothesis (Frisch et al., 1970, Science 109:397). Frisch additionally proposed that adipose tissue is a direct regulator of female reproduction since it converts androgens to estrogens via aromatization (R. E. Frisch, 1990, Adipose Tissue and Reproduction Progress in Reproductive Biology and Medicine, vol. 14 and Sifteri, 1981, J. Endocrinol. 89:119).
Radical treatments to treat obesity include surgical procedures such as liposuction and stomach stapling. In addition, numerous drugs have been utilized in an effort to regulate a person""s metabolism and/or to decrease appetite. Many of such drugs, however, have demonstrated harmful effects and have since been taken off of the market. Other to replacement drug therapies have proven less effective, and the long term health consequences of such drugs are unknown. For the underweight individual, who may be suffering from undesired weight loss due to a disease such as cancer or AIDS, efforts to maintain or gain weight can be equally problematic.
Faced with such a long felt, but unsolved need for simple and effective methods for regulating body weight and for treating conditions associated with dysregulation of body weight, researchers, over the last several decades, have expended literally hundreds of millions of dollars to investigate compounds that can be used to treat body weight problems such as obesity without the negative implications experienced with other, previously tested, weight regulating drugs. While altering appetite can affect weight, so can the regulation of the fat stores in adipose tissue. This latter approach has been an under-appreciated field relative to regulation of appetite. For instance, compared to the list of compounds directed at inhibition of energy uptake (appetite suppressants), very few compounds have been identified which stimulate fat mobilization or suppress lipid sequestration.
Physiologists have postulated for years that, when a mammal overeats, the resulting excess fat stores signal to the brain that the body is obese which, in turn, causes the body to eat less and burn more dietary fat. G. R. Hervey, Nature (London), 227:629-631(1969). This model of feedback inhibition is supported by parabiotic experiments, which implicates circulating hormones controlling adiposity. Genetic studies in model organisms, especially the mouse, have allowed the identification of molecules important for the regulation of body weight. These include leptin (Zhang et al., 1995, Nature 372:425-432, incorporated herein by reference in its entirety), a leptin receptor (Tartaglia et al., 1995, Cell 83:1263-1271) and a melanocortin receptor (Huszar et al., 1997, Cell 88:131-141).
Findings from several lines of investigations have placed proopiomelanocortin (POMC) and the peptides derived from it at a pivotal position in the central pathways for energy homeostasis. Obesity in the autosomal dominant lethal yellow (Ay/a) mouse, for example, is caused by ectopic expression of the agouti protein in the brain, where it antagonizes the melanocortin receptor 4 (MC4-R), a receptor found within the central nervous system (Lu et al., 1994, Nature 371:799-802). Agouti-related protein (AgRP) is normally expressed in the brain and antagonizes MC4-R. In transgenic mice, overexpression of AgRP results in obesity (Graham et al, 1997, Nat. Genet. 17:273-274 and Ollmann et al., 1997, Science 278:135-138). Targeted deletion of the MC4-R produces obesity similar to that of Ay mice, which is characterized by both adult onset obesity and increased linear growth (Huszar et al., 1997, Cell 88:131-141). Pharmacological evidence has further suggested the importance of a melanocortinergic pathway in the central regulation (i.e., via the central nervous system) of energy balance: decreased feeding was observed after central at administration of an MC4-R agonist (xcex1-MSH analog) to normal mice and increased feeding after central administration of a synthetic MC4-R antagonist to normal mice when measured for 12 hours (Fan et al., 1997, Nature 385:165-168). Further demonstrating the focus of previous investigators on the central pathways of energy homeostasis, PCT Publication WO 97/47316 and corresponding U.S. Pat. Nos. 5,908,609 and 5,932,779 to Lee et al., which are incorporated herein by reference in their entireties, disclose drug screening assays and diagnostic and therapeutic methods for treating body weight disorders by targeting the MC4-R. Lee et al. describe identifying compounds that target MC4-R and describe administering such compounds so that delivery to the brain is optimized.
Understanding of the regulation of fat stores was greatly advanced by the discovery of leptin, the gene affected in the obese (ob) mutation. Leptin is secreted by adipose tissue, and its levels increase with increasing fat stores. Leptin is known to have both central and peripheral effects. There are high affinity receptors for leptin in the hypothalamus. Absence of either leptin or the leptin receptor leads to morbid obesity, presumably because the hypothalamus receives no fat signal, and accordingly acts as if the animal is completely without fat stores, and in some manner directs adipocytes to accumulate fat. The use of leptin to treat obesity in mice,.however, requires very high, non-physiological doses. Thus, leptin alone has not been found to be a particularly useful antiobesity agent.
To treat wasting and cachexia in patients such as the elderly, AIDS patients and cancer patients, anabolic steroids, growth hormone, dietary regimens, erythropoietin, cytokine therapy and anti-cytokine therapy, among other therapies, have been used to try to improve the condition of such patients. Such therapies cross a wide range of target cells, may have undesirable systemic side effects, may require toxic doses to work, and may not be sufficient to completely address the complex biological dysfunction related to different types of wasting disorders, however, and therefore, research is ongoing in the effort to find additional solutions to this problem.
Therefore, there remains a need in the art for a simple, safe and effective method for controlling body weight and for treating conditions related to or caused by undesired and/or health compromising body weight.
While a majority of the prior art methods to regulate body weight have involved the regulation of appetite (i.e., by regulation of central pathways of energy homeostasis), the present invention is primarily directed to the regulation of the fat stores in adipose tissue (i.e., peripheral pathways of energy homeostasis). The present invention is specifically directed to a method and compound for controlling body weight (i.e., decreasing body weight, reducing weight gain, increasing body weight, or reducing weight loss) and conditions associated with or caused by undesirable body weight. Such a method comprises administering to an animal that is at risk for or has undesired body weight and/or a detrimental condition related thereto a therapeutic composition that regulates the peripheral melanocortinergic pathway and/or the leptinergic pathway of energy homeostasis.
One embodiment of the present invention relates to a method to regulate body weight in an animal, comprising administering to the animal a therapeutic composition comprising a proopiomelanocortin (POMC) compound, wherein the POMC compound is administered to the periphery of the animal in an amount effective to measurably regulate body weight in the animal, whereby administration of the compound minimizes delivery of the compound to the central nervous system of the animal. The POMC compound can include, but is not limited to, a melanocortin compound and a lipocortin compound. In a preferred embodiment, the compound is a melanocortin compound. Melanocortin compounds can include, for example, melanocyte stimulating hormone (MSH), a fragment of MSH, a homologue of MSH, a peptide mimetic of MSH, a non-peptide mimetic of MSH, and a fusion protein comprising an MSH protein or fragment thereof. In one embodiment, the compound is selected from the group of xcex1-MSH, xcex2-MSH and xcex3-MSH. In another embodiment, the compound is a peptide mimetic of MSH. In a preferred embodiment, the compound,is an analog of a peptide having an amino acid sequence represented herein by SEQ ID NO:2.
In one embodiment, the POMC compound is an xcex1-MSH analog selected from the group of:
a. [Ac-Cys4, D-Phe7, Cys10]xcex1-MSH, wherein the Cys residues are connected by a disulfide bond;
b. Ac-[Nle4, Xaa5, HiS6, Xaa7, Arg7, Trp9, Xaa10]-NH2, (SEQ ID NO:3)
wherein Xaa5 is Glu or Asp, Xaa7 is Phe or D-Phe and Xaa10 is a dibasic amino acid; Lys; ornithine; 2,4,-diaminobutyric acid; or 2,3 diaminopropionic acid (Dpr);
c. Ac-[Cys4, Cys10]xcex1-MSH1-13NH2;
d. R1xe2x80x94Wxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94R2,
wherein R1 is selected from the group consisting of Ac-Gly-, Ac-Met-Glu-, Ac-Nle-Glu- and Ac-Tyr-Glu-;
W is selected from the group consisting of -His- and -D-His-;
X is selected from the group consisting of -Phe-, -D-Phe-, -Tyr, -D-Tyr-, (-pNO2)D-Phe7-;
Y is selected from the group consisting of -Arg- and -D-Arg-;
Z is selected from the group consisting of -Trp- and -D-Trp-; and,
R2 is selected from the group consisting of xe2x80x94NH2, -Gly-NH2, and -Gly-Lys-NH2;
e. Ac-Ser-Tyr-Ser-M-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (SEQ ID NO:4),
wherein M is selected from the group consisting of Met, Nle, and Cys;
f. [Nle4, D-Phe7]-xcex1-MSH;
g. [Nle4, D-Phe7]-xcex1-MSH4-10;
h. [Nle4, D-Phe7]-xcex1-MSH4-11;
i. [Nle4, D-Phe7, D-Trp9]-xcex1-MSH4-11;
j. [Nle4, D-Phe7]-xcex1-MSM4-9;
k. Ac-[Nle4, AA5, D-Phe7, AA10]-R1 or Ac-[Nle4, AA5, D-Phe7, AA11]-R2;
wherein AA5 may be either a L- or D-amino acid having an omega amino or carboxyl group in the side chain, e.g., xcex1,xcex3-daminopropionic acid, xcex1,xcex3-diaminobutyric acid, Orn, Lys, xcex1,xcex3-aminoadipic acid, xcex1-aminopimelic acid, or higher homologs, Glu or Asp;
wherein AA10 may be diaminopropionic acid, xcex1,xcex3-diaminobutyric acid, Orn, Lys, xcex1,xcex2-amninoadipic acid, xcex1-aminopimelic acid, or higher homologs, Glu or Asp;
wherein R1 is the designation xcex1-MSH1-13NH2, xcex1-MSH1-12NH2, xcex1-MSH1-11NH2, xcex1-MSH4-13NH2, or xcex1-MSH4-10NH2;
wherein AA11 may be L- or D-amino acid having an omega-amino or carboxyl group in the side chain, e.g., xcex1,xcex2-diaminopropionic acid; xcex1,xcex3-diaminobutyric acid, Orn, Lys, xcex1-aminoadipic acid, xcex1-aminopimelic acid, or higher homologs, Glu or Asp;
wherein R2 is the designation xcex1-MSH1-13NH2, xcex1-MSH1-12NH2, xcex1-MSH1-11NH2, xcex1-MSH4-13NH2, or xcex1-MSH4-10NH2; and,
wherein Xxx may be from 1 to 5 xcex1-amino acid residues each of which may be of L- or D- configuration, or a linear or branched chain spacer; 
wherein R1 is a substituted or unsubstituted aromatic radical;
R2 is hydrogen or a methyl group;
R3 is a carboxylate, carboxamide, hydroxymethyl, or aldehyde group;
R4 is glutaric acid, alanine, -amino butyric acid, valine, leucine or isoleucine;
R5 is histidine, glutamic acid, alanine, valine, leucine or isoleucine;
R6 and R7, which may be the same or different, are hydrogen, methyl or lower alkyl having one to five carbon atoms;
R8 and R9, which may be the same or different, are hydrogen, methyl or lower alkyl having one to five carbon atoms;
X and Y are sulfur, methylene, SO or SO2;
Z is xe2x80x94NH2, 
and,
n is an integer greater than or equal to 2; 
wherein R1 is phenyl, indole, phydroxyphenyl, p-aminophenyl, imidazole, 1-naphthyl adamantyl or alkylphenyl, 2-naphthyl;
R2 is hydrogen or a methyl group;
R3 is a carboxylate, carboxamide, hydroxymethyl, or aldehyde group;
X and Y are sulfur, methylene, SO or SO2;
Z is xe2x80x94NH2, 
xe2x80x83and,
n is an integer greater than or equal to 2; and wherein the cyclized portion of the compound is conformationally restricted in a manner which is compatible with the reactivity of the compound with receptors of the central nervous system. In one aspect, the POMC compound is a peptide comprising an amino acid sequence represented by SEQ ID NO:1.
A POMC compound preferably has the following identifying characteristics: (1) an ability to bind to a POMC receptor that is expressed in peripheral tissues; and, (2) a biological activity selected from the group consisting of stimulation of lipolysis and inhibition of the uptake of fatty acids by adipocytes. The POMC receptor is preferably selected from the group of melanocortin 2-receptor (MC2-R) and melanocortin 5-receptor (NC5-R), with MC2-R being more preferred. In one embodiment, the POMC compound binds to a melanocortin receptor selected from the group consisting of MC2-R and melanocortin 5-receptor (MC5-R), with a higher affinity than to melanocortin4 receptors (MC4-R). In another embodiment, the compound binds to a melanocortin receptor selected from the group consisting of MC2-R and melanocortin 5-receptor (MC5-R), and does not bind to any other melanocortin receptor under physiological conditions. In another embodiment, the compound binds to MC2-R, and does not bind to any other melanocortin receptor under physiological conditions. In yet another embodiment, the compound does not bind to MC4-R under physiological conditions. Preferably, the compound preferentially activates melanocortin-2 receptors (MC2-R) as compared to melanocortin4 receptors (MC4-R). In one embodiment, compound does not activate MC4-Runderphysiological conditions.
Preferably, administration of the compound is insufficient to cause a statistically significant change in the appetite of the animal as compared to before administration of the compound.
The therapeutic composition can be administered by a route selected from the group consisting of transdermally, topically, parenterally and orally. Preferably, the therapeutic composition is not administered directly to the central nervous system of the animal. In one embodiment, the therapeutic composition is administered in a controlled release formulation. A POMC compound is preferably administered in a dose of from about 0.1 xcexcg to about 10 mg per kg body weight of the animal, and in another aspect, in a dose of from about 1 xcexcg to about 10 mg per kg body weight of the animal. In one aspect, the POMC compound is administered in a dose of from about 40 xcexcg to about 1 mg per kg body weight of the animal. Preferably, the POMC compound is from about 0.1% to about 90% of the therapeutic composition by weight, and in one embodiment, the POMC compound is from about 0.1% to about 1% of the therapeutic composition by weight. In one embodiment, the composition further comprises an antagonist of MC4-R. In another aspect, the composition further comprises an agent that inhibits binding of the POMC compound to an MC4-R. In another aspect, the composition further comprises an agent which inhibits the POMC compound from entering the central nervous system of the animal.
In one embodiment, the method is effective to measurably decrease body weight in the animal. A decrease in body weight in the animal can be measured within at least about two weeks of the step of administering the compound, and more preferably at least about one week, and more preferably at least about 3 days, and even more preferably at least about 24 hours of the step of administering the compound.
A preferred animal to which to administer the POMC compound includes an animal that has serum leptin levels between about 0 ng/ml and 50 ng/ml prior to the step of administration, and/or an animal that has serum MSH levels between about 0 ng/ml and 10 ng/ml prior to the step of administration. In one aspect, the animal has a ratio of serum MSH levels to serum leptin levels of greater than about 1:100 prior to the step of administration. In another aspect, the animal is a human having a body mass index (BMI) of greater than 27 kilograms per square meter.
In one embodiment, the composition further comprises another body weight regulating agent. Preferably, the body weight regulating agent is leptin. In this embodiment, the composition comprises a ratio of the POMC compound to leptin of about 1:100. In another aspect, the composition comprises the leptin in a dose of from about 0.1 xcexcg to about 100 mg per kg body weight of the animal.
In another embodiment of the method of the present invention, the therapeutic composition is administered in an amount effective to measurably increase body weight in the animal or to decrease body weight loss in the animal. In one embodiment of this aspect of the present method, the POMC compound is combined with another body weight regulating agent. Such a body weight regulating agent can include, but is not limited to, an anabolic steroid, a growth hormone, erythropoietin, a cytokine, and an anti-cytokine agent. In this embodiment, the POMC compound is a proopiomelanocortin (POMC) antagonist compound. Preferably, the compound has the following identifying characteristics: (1) an ability to bind to a POMC receptor that is expressed in peripheral tissues; and, (2) a biological activity selected from the group consisting of inhibition of lipolysis and stimulation of the uptake of fatty acids by adipocytes. Preferably, the receptor is selected from the group of melanocortin 2-receptor (MC2-R) and melanocortin 5-receptor (MC5-R), with MC2-R being more preferred. Preferably, the antagonist compound is selected from the group consisting of a melanocortin antagonist compound and a lipocortin antagonist compound, with melanocortin antagonist compounds being more preferred. In one aspect, the antagonist compound is selected from the group of a fragment of MSH having MSH antagonist action, a homologue of MSH having MSH antagonist action, a peptide mimetic of MSH having MSH antagonist action, a non-peptide mimetic of MSH having MSH antagonist action, and a fusion protein comprising any of the MSH antagonist compounds. Preferably, the antagonist compound is selected from the group of xcex1-MSH antagonist, xcex2-MSH antagonist and xcex3-MSH antagonist. In one aspect, the antagonist compound is a peptide mimetic of MSH. In another aspect, the antagonist compound is an MSH analog selected from the group consisting of: 
wherein R1 is a substituted or unsubstituted aromatic radical;
R2 is hydrogen or a methyl group;
R3 is a carboxylate, carboxamide, hydroxymethyl, or aldehyde group;
R4 is glutamic acid, alanine, -amino butyric acid, valine, leucine or isoleucine;
R5 is histidine, glutamic acid, alanine, valine, leucine or isoleucine;
R6 and R7, which may he the same or different, are hydrogen, methyl or lower alkyl having one to five carbon atoms;
R8 and R9, which may be the same or different, are hydrogen, methyl or lower alkyl having one to five carbon atoms;
X and Y are sulfur, methylene, SO or SO2;
Z is xe2x80x94NH2, 
xe2x80x83and,
n is an integer greater than or equal to 2; and, 
wherein R1 is phenyl, indole, p-hydroxyphenyl, p-aminophenyl, imidazole, 1-naphthyl adamantyl or alkylphenyl, 2-naphthyl;
R2 is hydrogen or a methyl group;
R3 is a carboxylate, carboxamide, hydroxymethyl, or aldehyde group;
X and Y are sulfur, methylene, SO or SO2;
Z is xe2x80x94NH2, 
xe2x80x83and,
n is an integer greater than or equal to 2; and wherein the cyclized portion of the compound is conformationally restricted in a manner which is compatible with the reactivity of the compound with receptors of the central nervous system.
Preferably, in the method of the present invention, the animal is a human.
Another embodiment of the present invention relates to a method for inhibition of free fatty acid uptake and/or stimulation of lipolysis in an animal, comprising administering to the periphery of an animal a POMC compound in an amount effective to produce a result selected from the group consisting of stimulation of lipolysis and inhibition of fatty acid uptake. In this embodiment, the amount is preferably insufficient to cause a statistically significant change in the appetite of the animal after administration of the compound as compared to before administration of the compound. Various aspects of such a method are as described for the methods above.
Yet another embodiment of the present invention relates to a method of regulating the body weight of an animal, comprising administering to an animal a POMC compound in an amount effective to bind to POMC receptors expressed by the animal in the animal""s peripheral tissues, the effective amount: (a) being insufficient to substantially change the appetite of the animal after the step of administering as compared to before the step of administering; (b) being between about 0.1 xcexcg and about 10 mg per kg of body weight of the animal; (c) being sufficient to affect a biological activity selected from the group consisting of: (i) lip lysis; and, (ii) uptake of fatty acids by adipocytes in the animal; and, (d) being effective to measurably increase or decrease the body weight of the animal after the compound has been administered to the animal. Various aspects of such a method are as described for the methods above.
Another embodiment of the present invention relates to a method to regulate body is weight in an animal, comprising modulating the activity of a melanocortin receptor selected from the group consisting of melanocortin 2-receptor and melanocortin 5-receptor. In this embodiment, the melanocortin receptor is preferably a melanocortin 2-receptor. The step of modulating can include administering to the periphery of the animal a compound which regulates the melanocortin receptor. The compound can include, but is not limited to a POMC compound, an antibody that selectively binds to the melanocortin receptor, and a soluble melanocortin receptor. The step of modulating can include, in one embodiment, administering an effective amount of a compound that increases expression of the melanocortin 2-receptor and induces weight loss. The step of modulating preferably comprises administering an effective amount of a compound that decreases expression of the melanocortin 2-receptor and induces weight gain. Various aspects of such a method are as described for the methods above.
Yet another embodiment of the present invention relates to a method for regulating metabolic efficiency in an animal, comprising: (a) measuring serum MSH levels in an animal; (b) identifying animals having serum MSH levels of less than about 0.1 ng/ml; and, (c) administering to the periphery of the animals identified in (b) a composition comprising a compound selected from the group consisting of a POMC compound and leptin, wherein the compound is administered in an amount effective to increase serum MSH levels in the animal to level effective to produce a result selected from the group consisting of stimulating lipolysis and inhibiting fatty acid uptake in the animal. Preferably, the compound is administered in an amount effective to produce a measurable decrease in body weight of the animal. Various aspects of such a method are as described for the methods above.
Another embodiment of the present invention relates to a therapeutic composition that regulates the peripheral melanocortinergic and/or leptinergic pathways of energy homeostasis in an animal, comprising: (a) a first body weight regulating agent that is a proopiomelanocortin (POMC) compound; and, (b) a second body weight regulating agent that is not a proopiomelanocortin (POMC) compound. The POMC compound is preferably a POMC compound as described above, preferably provided in the doses and formulated as described above. In one embodiment, the second body weight regulating agent is leptin. Preferably, the composition comprises a ratio of the POMC compound to leptin of 1:100, and in another aspect, a ratio of the POMC compound to leptin of 1:25, and in another aspect, a ratio of the POMC compound to leptin of 1:10. The dose of leptin is preferably from about 0.1 xcexcg to about 100 mg per kg body weight of the animal, and more preferably, from about 0.1 xcexcg to about 10 mg per kg body weight of the animal, and in another aspect, is from about 1 xcexcg to about 10 mg per kg body weight of the animal. In another embodiment, the second body weight regulating agent is selected from the group consisting of an anabolic steroid, a growth hormone, erythropoietin, a cytokine, and an anti-cytokine agent. The therapeutic composition preferably further comprises a pharmaceutically acceptable excipient. Such a pharmaceutically acceptable excipient can, in one embodiment, prolong the presence of the therapeutic composition in the bloodstream of a animal.
Yet another embodiment of the present invention relates to a method for treating an affective and mood disorder in an animal, comprising administering to an animal at risk for or suffering from an affective mood disorder a therapeutic composition comprising a proopiomelanocortin (POMC) compound, wherein the POMC compound is administered to the periphery of the animal in an amount effective to measurably ameliorate the disorder in the animal, whereby administration of the compound minimizes delivery of the compound to the central nervous system of the animal. The affective and mood disorder can include, but is not limited to, depression and dysthymia. In one aspect, the depression is atypical depression.
Another embodiment of the present invention relates to a method to treat an obesity-associated disorder in an animal, comprising administering to an animal suffering from or at risk for an obesity-associated disorder a therapeutic composition comprising a proopiomelanocortin (POMC) compound, wherein the POMC compound is administered to the periphery of the animal in an amount effective to measurably decrease body weight or weight gain in the animal, whereby administration of the compound minimizes delivery of the compound to the central nervous system of the animal. The obesity-associated disorder can include, but is not limited to, non-insulin dependent diabetes mellitus, cardiovascular disease, cancer, hypertension, osteoarthritis, stroke, respiratory problems, and gall bladder disease.
Another embodiment of the present invention relates to a method for treating a reproductive disorder in an animal, comprising administering to an animal at risk for or suffering from a reproductive disorder a therapeutic composition comprising a proopiomelanocortin (POMC) compound, wherein the POMC compound is administered to the periphery of the animal in an amount effective to prevent or ameliorate the disorder, whereby administration of the compound minimizes delivery of the compound to the central nervous system of the animal. In one embodiment, the reproductive disorder includes, but is not limited to, amenorrhea, an inability or reduced ability to ovulate, an inability to conceive, an inability or reduced ability to maintain a pregnancy, an inability or reduced ability to lactate, an inability or reduced ability to deliver a full-term offspring, and an inability or reduced ability to impregnate a female.
Yet another embodiment of the present invention relates to a method to control undesired body weight which is a side effect resulting from administration of a pharmaceutical compound, comprising administering to an animal at risk for suffering from undesired body weight which is a side effect resulting from administration of a pharmaceutical compound, a therapeutic composition comprising a proopiomelanocortin (POMC) compound wherein the POMC compound is administered to the periphery of the animal in an amount effective to measurably decrease body weight or weight gain in the animal, whereby administration of the compound minimizes delivery of the compound to the central nervous system of the animal. In one embodiment, the pharmaceutical compound includes, but is not limited to, valproic acid, lithium, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRI).
Another embodiment of the present invention relates to a food composition that regulates the peripheral melanocortinergic and/or leptinergic pathways of energy homeostasis, comprising a proopiomelanocortin (POMC) compound. Preferably, the food composition is effective to measurably regulate body weight in the animal, and wherein delivery of the compound to the central nervous system of the animal is minimized.
Yet another embodiment of the present invention relates to a method to increase the body weight and/or mass in an animal having an eating disorder, comprising administering to the animal a therapeutic composition comprising a proopiomelanocortin. (POMC) antagonist compound, wherein the POMC compound is administered to the periphery of the animal in an amount effective to measurably increase body weight or reduce body weight loss in the animal, whereby administration of the compound minimizes delivery of the compound to the central nervous system of the animal. In one embodiment, the eating disorder is selected from the group consisting of anorexia and bulemia.